Related Experiment Video
Updated: Mar 13, 2026
Author Spotlight: Advancing Tendon Research by Developing Mouse Assembloids to Understand Cellular Mechanisms
Published on: March 22, 2024
AMP-Activated Protein Kinase and Sirtuin 1 Coregulation of Cortactin Contributes to Endothelial Function
Tzu-Pin Shentu1, Ming He1, Xiaoli Sun1
1From the Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (T.-P.S., M.H., J.Z., J.Z.; L.W., J.Y.-J.S.); Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China (X.S., Y.Z.); Department of Chemistry, University of California, Riverside (F.Z., Y.W.); Department of Cardiopulmonary Sciences, Schools of Allied Health, Loma Linda University, CA (B.G., T.L.M.); Department of Kinesiology and Health Sciences, California State University, San Bernardino (G.G.G.); and Division of Biomedical Sciences, University of California, Riverside (D.A.J.).
Objective:
Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress.
Approach And Results:
Analysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation. Mass spectrometry confirmed Thr-401 as the site of AMPK phosphorylation. Immunoblot analysis with AMPK siRNA and SIRT1 siRNA in human umbilical vein ECs and EC-specific AMPKα2 knockout mice showed that AMPK phosphorylation of cortactin primes SIRT1 deacetylation in response to shear stress. Immunoblot analyses with cortactin siRNA in human umbilical vein ECs, phospho-deficient T401A and phospho-mimetic T401D mutant, or aceto-deficient (9K/R) and aceto-mimetic (9K/Q) showed that cortactin regulates endothelial nitric oxide synthase activity. Confocal imaging and sucrose-density gradient analyses revealed that the phosphorylated/deacetylated cortactin translocates to the EC periphery facilitating endothelial nitric oxide synthase translocation from lipid to nonlipid raft domains. Knockdown of cortactin in vitro or genetic reduction of cortactin expression in vivo in mice substantially decreased the endothelial nitric oxide synthase-derived NO bioavailability. In vivo, atherosclerotic lesions increase in ApoE-/-/cortactin+/- mice, when compared with ApoE-/-/cortactin+/+ littermates.
Conclusions:
AMPK phosphorylation of cortactin followed by SIRT1 deacetylation modulates the interaction of cortactin and cortical-actin in response to shear stress. Functionally, this AMPK/SIRT1 coregulated cortactin-F-actin dynamics is required for endothelial nitric oxide synthase subcellular translocation/activation and is atheroprotective.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
01:24Regulation of Angiogenesis and Blood Supply
01:28Nitric Oxide Signaling Pathway
01:25cAMP-dependent Protein Kinase Pathways
01:16Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:07MAPK Signaling Cascades